interpreted with caution as aggregated data on CVC insertion and hand hygiene compliance had to be used and other factors could be relevant [40‐42]. Our study has several strengths. The multicenter design with 14 hospitals from 11 different countries embraces a range of variable IPC practices across Europe, and thus offers greater generalizability than previous studies. The number of CVC‐days observed in each center was large and the combination of a shared baseline and intervention period and the randomized, stepped wedge introduction of the interventions helped to control for unknown trends and confounders. Lastly, the measurement of process indicators demonstrated that CRBSI reduction was the result of improved practice, even if some of this occurred before the formal intervention. The study has limitations. First, our stepped‐wedge design did not allow block randomization based on baseline rates. As a consequence and unfortunately, the CVCi arm had four out of the five hospitals with low baseline incidence densities. The small effect of the prevention program on CRBSI in the CVCi arm, that was significant in the before‐and‐after analysis, but not significant when considering the decreasing trend already observed during baseline, could well be due to the low baseline rate (1.4/1000 CVC‐days), which may be partly explained by the overrepresentation of cardiothoracic surgery patients undergoing elective CVC insertions in this study arm. Second, process indicators not only improved in allocated arms, but in all study arms (HH in the CVCi arm; CVC insertion score in the HHi arm). The PROHIBIT project was a priority or the only ongoing patient safety project in many of our centers. Such project prioritization, together with Hawthorne effects [43] due to the surveillance of process indicators, may have contributed to this finding. Third, some patient‐ and CVC characteristics differed between baseline and intervention, and between the study arms. Although significance of many differences are due to large numbers, cardiothoracic patients and hence scheduled surgical admissions were more frequent in the CVCi arm. While we could not adjust for severity‐of‐illness score for the entire study population due to missing data, all other critical variables were taken into account in the multivariable models. The analysis on the subset where Apache II scores were reported showed comparable results (Supp.Methods and results). Fourth, although the study duration was 30 months in total, we did not go back to the hospitals to test for sustainability. Others have shown sustainable effects of behavioral change studies aiming at CLABSI prevention[44]. In conclusion, this study demonstrates that multimodal prevention strategies aiming at improving CVC insertion practice and hand hygiene compliance reduce CRBSI in culturally diverse European ICUs. The CVC insertion score explained the reduction of CRBSI and helped to explain the dynamics of behavior change. Future quality
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